BG60496B2 - Method for the preparation of structural homogenous forms of thiazole derivatives - Google Patents

Abstract

The invention relates to two structurally homogeneous forms of famotidine with the chemical name n-sulfamoyl-3-(2-guanidinothiazol-4-yl-methylthio)-propionamides n. The specified forms of famotidine are obtained by selective crystallization or precipitation. 1 claim

Description

The invention relates to a method for the preparation of structurally homogeneous famotidine.

Famotidine is known to be chemically named M-sulfamoyl-3 - [(2-guanidino-thiazol-4-yl-methylthio) -propionamidine], whose name according to Chemical Abstracts is 3 - (((((2-diamino-methylene) ) amino) -4-thiazolyl) methyl) thio) -sulfamolylpropionamidine has an excellent blocking effect on the histamine H ₂ receptor. The polymorphic forms of famotidine have not been described in the literature.

During the study of known methods for the preparation of famotidine in the analysis of the compounds obtained by these methods by DSC (differential scanning calorimetry), it was found that famotidine has two forms, for example forms A and B. The site of the endothermic maximum of these forms , determined at a heating rate of 1 ° C / min, for Form A at 167 ° C and for Form B at 159 ° C.

In parallel experiments, compounds were found to always differ in some degree from each other, mainly in their bulk density and adhesiveness, and in addition, there was a large difference in their infrared spectra. During ordinary experiments, the characteristics of the compounds were varied arbitrarily and within a wide range. This is confirmed by the patent of ES No. 536 803 (INKE Co) with infrared spectroscopy data, according to which the adsorption bands at 3500, 3400 and 1600 cm ¹ according to the measurements made correspond to the form B, which has a lower melting point, and the band at 3240 cm ² corresponds to Form A with the higher melting point. The mixed nature of the compound is also evidenced by the adsorption strip at 1000 cm ', which may result from the fusion of the bands at 1005 and 986 cm ² of Form A and of the bands at 1009 and 982 ¹ of Form B. The mixed nature of the compound may be confirmed by comparing the DSC data given in the introduction with the melting point data (162 ° - 164 °) of the higher ES patent cited, as well as the melting point 158 ° - 164 ° C published in EP No. 128 736. Obviously, in both cases, the researchers had a mixture of form A and Form B with undefined composition.

In the manufacture of pharmaceuticals, very often manufacturers do not pay particular attention to structure, since in many cases the assumption is maintained that the identity of structural formulas implies the identity of different forms from a pharmaceutical point of view. This claim is supported, for example, for steroid compounds. However, in some cases there are significant differences in the biological activity of the various forms, such as in the case of mebendasol [Janssen Pharmaceutica: Clin. Really. Reports No. R 17635/36 (1973)], or significant differences can be found with respect to other parameters. Famotidine is one of the most typical representatives of these compounds.

The purpose of this research is to elucidate the reasons for the different characteristics of the individual famotidine samples and to develop a method for the preparation of various forms of famotidine with the required morphological purity.

In the first part of the scientific experiments, the relationship between the morphological properties of compounds obtained by crystallization using a solvent from those commonly used in pharmaceutical production was investigated, taking into account the solubility parameters of famotidine. No solvent has been found to ensure only one of the forms in all circumstances, but it has been found that, in the presence of organic solvents, form B is usually difficult to obtain.

After these studies, the influence of the kinetic conditions of crystallization was monitored and it was found that this was the parameter that determined the morphological properties of the compound obtained.

When examining the relationship between the mor2ological properties of the famotidine obtained and the kinetic conditions of its preparation, it was found that it is most advantageous to obtain form A if crystallization is carried out by exiting hot solution and at a low cooling rate. Conversely, if the product is obtained by crystallization by precipitation, caused by rapid saturation, the resultant compound exhibits the characteristics of the lower melting Form B.

Rapid saturation can be obtained by rapidly cooling the famotidine solution or by rapidly releasing the famotidine base from its salt.

In the case of rapid cooling using larger volumes, it can be considered as an element of uncertainty that the rate of formation of crystalline nuclei of Forms A and B depends on the chemical composition of the starting materials.

In the second possibility of rapid crystallization, i. releasing the famotidine base from its salts, in an environment with a pH lower than 3, the amidine group is very prone to hydrolysis. Salt formed with carboxylic acid, especially acetic acid, has been found to be particularly preferred. The famotidine base can be released from it with ammonium hydroxide by the reverse dosing method.

The invention relates to form A of famotidine, characterized in that its endothermic maximum melting point is at 167 ° C according to differential scanning calorimetry; the characteristic and adsorption bands in the infrared spectrum are at 3450, 1670, 1138 and 611 cm ¹ and its melting point is 167 ° - 170 ° C.

The invention also relates to Form B, which is characterized by its endothermic maximum melting point at 159 ° C according to DSC; its characteristic adsorption bands are at 3506, 3103 and 777 cm ¹ and its melting point is 159-162 ° C.

The invention also relates to a method for the preparation of structurally homogeneous famotidine. The method consists of dissolving famotidine with any structural composition in water and / or in a lower aliphatic alcohol upon heating, such as:

(a) when form A is obtained, the hot saturated solution crystallizes at a cooling rate of about 1 ° C / min or less; and

B) when Form B is obtained, the compound is obtained by precipitation from its saturated solution, which is obtained at a temperature lower than 40 ° C.

In both cases, the compound is isolated from the resulting suspension of its crystals. Alcohols with 1 to 8 carbon atoms are referred to as lower alcohols. They are straight or branched and have 0, 1 or 2 double bonds, for example methanol, ethanol, isopropanol, crotyl alcohol and the like.

In one embodiment of the invention, the saturated solution is obtained either by cooling the hot solution at a rate greater than 10 ° C / min or by releasing the basic form of famotidine from its salt.

The filtration of the compound obtained by the method is carried out at a temperature between 10 ° and 20 ° C and the most preferred temperature is in the range between 10 ° and 20 ° C.

The basic form can be obtained by the addition of the acetic acid-derived famotidine salt to ammonium hydroxide.

A high cooling rate can be achieved by adding ice or dry ice.

It is advantageous to add already formed crystalline embryos of the desired form to the system before crystallization begins.

The famotidine form A obtained by the process of the invention has an endothermic maximum melting point (on the DSC curve) of 167 ° C; the characteristic adsorption bands of its infrared spectrum are at 3450, 1670, 1138 and 611 cm @ -1.

Formot B of famotidine prepared by the process of the invention has an endothermic maximum melting point (on the DSC curve) of 159 ° C; the characteristic adsorption bands of its infrared spectrum are at 3506, 3103 and 777 cm '.

The greatest advantage of the method according to the invention is that it provides an easy, well-controlled technology for obtaining various forms of famotidine with 100% structural purity and accuracy3

but the separation of famotidine structural forms from one another and from polystructural mixtures of undefined composition. In order to show the importance of the homogeneous structures described in comparison with the polystructural mixtures, Data on the measurements of the pure forms A and B of famotidine are given. All data correspond to samples taken from an industrial scale sample according to Examples 1/5 and P / 5.

Table 1

A. Infrared data

Form A Form B 3452, 3408, 3240, 1670, 1647, 1549, 1138, 1005, 984, 906, 611 and 546 cm ¹ 3506 3400 3337 3103 1637, 1533, 1286, 1149 1109, 982, 852, 777, 638 and 544 cm '

C. Data from DSC measurements

The measurements were performed on a Perkin-Elmer apparatus in a nitrogen atmosphere. The DSC curves taken at a predetermined 25 heating rate determine the following parameters: maximum position, intersection point of the tangent drawn to the inflection point of the ascending branch of the curve and the baseline, and the onset and value of the enthalpy of melting calculated from the area locked by the curve. The units of measurement in the Max and Home columns are in ° C and the Enthalpy column in J / g.

Heating rate in ° C / min Form A Form B Max. begining Enthalpy Max begining Enthalpy 10 172,7 171,0 159,2 164,3 162,1 149,4 5 172,2 170,8 159,0 163.5 161,9 147.9 1 166,6 165,4 138.6 158.7 157.5 138.1 1 164,3 163,3 132,9 165,2 154.9 130.1 1 160,3 159.6 113,1 152,8 152,0 128,9

C. X-ray study data

The data presented here is obtained with a Philips apparatus and shows the distances of the layers measured in A.

Form A Form B 8.23, 6.29, 5.13, 4.78, 4.44, 4.30 (base), 4.29, 3.79, 3.43, 2.790 and 2.675 14.03, 7.47, 5.79, 5.52, 4.85, 4.38, 3.66 (base), 2.95 and 22.755

D. Bulk density

Form A Form B Without compaction 695 g / l 340 g / l With compaction 960 g / l 505 g / l Compaction ratio 1.38 1.47

The compaction was done with a manual vibrator for 5 min.

F. Tendency to adhere and form a non-homogeneous surface (projections and indentations)

Form A Form B does not form protruding powdery strongly bulging adhesives in the flakes

F. Rolling Angle Measurement Data

The data were obtained by measuring according to the following scheme. The mold to be tested is poured into a funnel equipped with a tube with a diameter of 5 mm, after which the funnel is placed in such a position that its opening is 10 cm above the level of the test substance. The cone angles that are formed mainly by the nipples as they exit the funnel are:

Form A Form B 41-42 ° C above 55 ° C *

In Form B, no correct data on the rolling angle can be obtained, because at 80-85 ° C the particles begin to accumulate along the inclined wall of the funnel and the resulting aggregates of 1-2 mm leave the wall. The above data correspond to the observations.

G. Deformation ratio of crystals

The deformation ratio represents the relation between the longitudinal axis and the largest diameter of the crystal.

The parameter was determined by measuring 250 - 250 grains and averaging the results.

Form A Form B 1,40 4.70

N. Solubility data

Solubility to give a saturated solution.

The studies are carried out as follows. The individual forms were dissolved with stirring for 5 h and the concentration of the substance in the solution was determined by ultraviolet spectroscopy at a wavelength of 277 nm.

Form A Form B 860 mg / l 980 mg / l

Dynamic solubility

The studies are carried out as follows. 10-10 mg of the form to be tested are added to 100 ml of distilled water with stirring. Samples are taken at certain times and, after filtration and appropriate dilution, the amount of dissolved famotidine is determined by ultraviolet spectroscopy.

Time Form A Form B 2 min 19 mg / l 25 mg / l 5 min 25 mg / l 40 mg / l 10 min 42 mg / l 51 mg / l 1 h 72 mg / l 76 mg / l

1. Thermodynamic stability

The studies are carried out as follows. Mixtures of the individual forms are prepared in a ratio of 95: 5 - for each form individually (with a very small amount of the other form). The mixtures were stirred with a magnetic stirrer for 24 h at 60 ° C, with water barely covering the crystals. The crystals are then filtered and subjected to structural testing. In both cases the compound turns out to be Form A.

Form A Form B stable unstable

From the observations described above, it can be concluded that the higher melting point form is Form A.

J. Electrostatic load

As it is not easy to perform the test in an organic chemical laboratory, the following data were obtained as follows. In a 120 mm diameter glass dish, place 37 g of one sample and grind for 1 min with a glass spatula. The substance is then poured from the dish without shaking, and the remaining substance adhered to the dish is weighed. The measurement is repeated, this time tapping the dish 10 times.

Form A Form B No knocking 2.8 g 13,0 g

By tapping 0.5 g 10,0 g

The data in the tables explain the advantages of the invention, but the results for a number of parameters are controversial.

1. It is best estimated by the infrared spectrum that over 3500 cm < 3 > only Form B has an adsorption strip. This is a characteristic strip that makes it possible to even detect 5% of Form B in Form A, even with a conventional optical spectrophotometer.

2. There is, roughly, a difference of about twice the bulk density, which means that for compounds of indeterminate structure, measurement by a graduated cylinder can give a significant error.

3. There is a difference of one order in the tendency to hold electrostatic charges in both forms. The amount of strongly adherent Form B is 20 times greater than the amount of Form A.

4. With respect to the rolling angle and the tendency to form a non-homogeneous surface (protrusions), the characteristic data differ not only in value but also in appearance. Only one structural structure or the other is capable of developing reliable packaging technology. This is not possible for structural mixtures of non-reproducible composition.

5. The deformation ratio values characterizing the shape of the crystals indirectly estimate the specific surface area, respectively, indicating the extent to which the crystals can adhere to each other, i.e. these values reflect the tendency to adhere and form scales. These Form B values are 3.3 times higher than Form A values.

6. Due to the high specific surface area described above, the dissolution rate of Form B is significantly higher than that of Form A. With respect to dissolution to form a saturated solution, the value of Form B is also significantly higher.

As famotidine is not yet included in the pharmacopoeia, for the time being, no definitive answer can be given as to which of the two forms described in the invention has better pharmaceutical characteristics. From the point of view of working with Form A and the stability of its parameters, it is preferable, but it should be remembered that when it comes to a pharmaceutical preparation, the rate of dissolution is extremely important, and it is higher in form IN.

The invention is illustrated by the following non-limiting examples. The examples in group I relate to the preparation of Form A, and the examples in Group II refer to the preparation of Form B.

Example 1/1. Famotidine 10 g of any structural composition, hereinafter referred to as famotidine, is dissolved in 100 ml of water under rapid boiling. The solution was allowed to cool from 100 ° C to 20 ° C for 3 h, then stirred for 30 min at 15 ° - 20 ° C and the precipitated crystalline substance of monoclinic prismatic form was filtered and dried. The yield was 9.4 g (94%), m.p. 167 ° - 169 ° C. Physico-chemical properties of the compound: DSC 167 ° C [at heating rate l ° C / min].

The most characteristic infrared adsorption bands are 3452, 3408, 3240, 1670, 1647, 1547,1549, 1138, 1005, 984, 906, 611 and 546 cm ¹ .

X-ray diffraction data (distance between layers in A): 8.23, 6.09, 5.13, 4.78, 4.44, 4.30 (basic), 4.24, 3.79 , 3.43, 2.790 and 2.675.

Example 1/2. Famotidine 10 g was dissolved in 70 ml of a 59% aqueous methanol solution by boiling and stirring. The solution at 78 ° C was clarified, filtered and cooled to room temperature for 3 h, then stirred for 30 min. In this way they are obtained

8.4 g of microcrystalline Form A, mp 167 ° - 169 ° C. Its physicochemical properties are similar to those given in Example 1/1.

Example 1/3. Famotidine (10 g) was dissolved hot in 50 ml of 50% aqueous ethanol with stirring. The solution was allowed to cool to room temperature for 3 h, then stirred for 1 h. Filtration and drying are obtained

9.5 g (95%) of Form A, mp 167 ° - 169 ° C. The physicochemical properties of the compound are similar to those given in Example 1/1.

Example 1/4. Famotidine 10 g was dissolved in 60 ml of a 50% aqueous solution of isopropanol under rapid boiling. The solution was allowed to homogenize for 3 h. The resulting crystals were filtered off and dried.

Weight of the substance obtained: 9.4 (94%).

Mp: 167 ° - 169 ° C.

The physicochemical properties of the compound are similar to those indicated in Example 1/1.

Example 1/5. A solution of 70 kg of famotidine, 427.5 kg of deionized water and 124 kg (157.5 I) of ethanol was prepared in a boiling and stirring apparatus of 1000 l. The resulting solution at 80 ° C was slowly cooled for 5 - 6 hours to 20 ° C with continuous stirring. The solution was stirred for 1 h at 15 ° - 20 ° C, then centrifuged and the product obtained was dried. 67 kg of Form A are obtained with a melting point of 167 ° - 170 ° C. The physicochemical properties of the compound are similar to those indicated in Example 1/1.

Example II / 1. Famotidine 10 g of randomly selected structural composition (hereinafter famotidine) is dissolved under rapid boiling and stirring in water. As soon as famotidine is dissolved, the solution begins to cool with continuous stirring in an ice bath. Form B is obtained in the form of needle crystals, which are filtered and dried. The weight of the resulting material was 9.4 g (94%) and the melting point was 159 ° - 161 ° C. The physicochemical properties of the compound are as follows: DSC 159 ° C [at heating rate l ° C / min],

The most characteristic infrared adsorption bands are 3506, 3400, 3337, 3103, 1637, 1533, 1286, 1149, 1109, 982, 852, 777, 638 and 544 cm ¹ .

X-ray diffraction data (distance between layers in A): 14.03, 7.47, 5.79, 5.52, 4.85, 4.38, 4.13, 3.66 (basic), 2,954, 2,755.

Example 11/2. Famotidine 5 g was dissolved in 40 ml of 75% aqueous methanol solution with rapid boiling and stirring continuously. The hot solution was filtered and the solution was poured onto ice while stirring the mixture. Stir for another 1 h. The crystallized, needle-shaped crystals of Form B are separated from the solution by filtration. Weight is

4.55 g (91%) and its melting point 159 ° - 161 ° C. The physicochemical properties of the compound are similar to those of Example 11/1.

Example 11/3. Famotidine 5 g was dissolved in 30 ml of a 50% aqueous solution of isopropyl alcohol under rapid boiling. The solution was then cooled rapidly with ice water and the resulting crystals of Form B were separated after 1 hour of stirring. The weight of the compound obtained after drying is 4.6 g (92%) and has a melting point of 156 ° - 162 ° C. The physicochemical properties of the compound are similar to those of Example II / 1.

Example 11/4. Famotidine 16.87 g was dissolved in a mixture of 125 ml water and 6.0 g glacial acetic acid for 15 minutes with stirring. The resulting solution was poured into a funnel with a faucet and poured drop-wise at a uniform rate over a stirring mixture of 10 ml (25%) of ammonia and 20 ml of water at a temperature of 20 ° - 25 ° C. Wait 10 minutes and filter the resulting compound, wash with water and dry. 15.8 g of Form B (93.7%) are obtained with a melting point of 159 ° - 162 ° C. The physicochemical properties of the compound are similar to those of Example 11/1. 25

Example II / 5. Famotidine 110 kg is dissolved in a mixture of 816 kg deionized water and

39.2 kg glacial acetic acid. The resulting and filtered solution was poured into a drip tank. 120 kg of deionized water and 60 kg of 25% ammonia are placed in a 2000 1 capacity unit equipped with a stirrer. Then 550 g of Form B crystals are added to water containing a solution of ammonium hydroxide, after which the solution of famotidine and acetate is transferred at a constant rate to the plant at 15 ° 25 ° C and stirred for 1 -

1.5 h. After stirring for an additional 30 min, centrifugation, washing and drying, 99.4 kg (90.4%) of Form B was obtained. Melting point was 159 ° - 162 ° C. The physicochemical properties of the compound are similar to those of Example II / 1.

Claims

Claims (1)

Formot B of famotidine, characterized in that its endothermic maximum melts at a temperature of 159 ° C according to DSC; the characteristic adsorption bands in its infrared spectrum are at 3506, 3103 and 777 cm ¹ and its melting point is 159 ° - 162 ° C. Publication of the Patent Office of the Republic of Bulgaria 1113 Sofia, Dr. Γ Blvd. M. Dimitrov 52-B